Prostate specific antigen (PSA) is recognized as a molecular marker for CAP. Blood or serum based immunoassays measuring the total PSA level have been commercially available for a number of years. However, the detection of total PSA does not necessarily mean that a patient has CAP. In order to distinguish CAP, a total PSA test has to satisfy two elements: a high sensitivity--the ability to detect disease when present, and a high specificity--the ability to detect true negatives and avoid false positives. From clinical experience, total PSA tests have become generally accepted as being predictive of CAP if the total PSA level is greater than 10.0 ng/mL. Total PSA values between 0.0 ng/mL and about 4.0 ng/mL have been considered generally predictive of no disease being present, with a reference value of about 3.5 ng/mL being used for men under 60 years old and about 2.5 ng/mL being used for men under 50 years old. (See Oesterling, J. E., Cooner, W. H., Jacobsen, S. J., Guess H. A., and Lieber, M. M.: "Influence of Patient Age on the Serum PSA Concentration and Important Clinical Observations": Urol. Clin. North Am.; Vol. 20: 671-680, 1993.)
PSA is primarily organ-specific, not cancer specific. Thus, PSA in blood or serum can result not only from CAP, but also from normal or hyperplastic prostate tissues. Historically, a total PSA test cannot reliably distinguish BPD from CAP at less than 10.0 ng/mL. Studies have found that 43% (136/319) of patients with organ-confined CAP have a total PSA value within the normal range of less than 4.0 ng/mL. Moreover, about 25% (148/597) of men with BPD have a total PSA value above 4.0 ng/mL. (See Oesterling, J. E.: "Prostate Specific Antigen: A Critical Assessment of the Most Useful Tumor Marker for Adenocarcinoma of the Prostate", J. Urol., Vol:145:907-923, 1991.) Standard medical practice is to biopsy men over 60 years of age having total PSA levels of between 4.0 ng/mL and 10.0 ng/mL because about 30% of those patients have CAP. Likewise, age specific reference ranges have been used for patients between 50 years and 60 years old whose total PSA falls between 3.5 ng/mL and 10.0 ng/mL and patients under 50 years old whose total PSA falls between 2.5 ng/mL and 10.0 ng/mL. These men are often biopsied under current medical practice.
One proposed method for detecting CAP is disclosed in U.S. Pat. No. 5,501,983 to Hans Lilja et alia. In general, the Lilja patent discloses using immunoassays to measure free PSA and a complexed form of PSA. Free PSA is a 33 kDa single chain glycoenzyme that is produced by the epithelial cells lining the acini and prostatic ducts of the prostate gland. Complexed PSA refers primarily to a 90kDa complex of PSA bound to alpha 1-antichymotrypsin (ACT) protein, an endogenous protease inhibitor. Free PSA and complexed PSA, and their proportions are applied in the diagnosis of patients with CAP. Throughout, the specification discloses using a combination of a free PSA to total PSA (F/T) proportion and a complexed PSA to total PSA (C/T) proportion for use in diagnosing CAP. No prostate needle biopsy were performed on the patients, and the patients covered a full range of total PSA values. The text provides no guidance as to specifically how one uses these proportions. It should be noted that the initial discovery of the protein designated as free PSA was reported by George Sensabaugh et alia in an article entitled "Isolation and Characterization of a Semen-Specific Protein from Human Seminal Plasma: A Potential New Marker for Semen Identification", J. Forensic Sci., 1978; 23:106-118. Therein, Sensabaugh disclosed the free PSA protein as the prostate protein "p30", having a molecular weight of about 30,000 daltons. This find was confirmed in U.S. Pat. No. 4,446,122 to Tsann M. Chu and Lawrence Papsidero, but here the protein was designated as "PA".
A significant advance in diagnosing BPD in a male human patient without requiring a biopsy is disclosed by Luderer, A. A., et alia in "Measurement of the Proportion of Free to Total Prostate-Specific Antigen Improves Diagnostic Performance of Prostate-Specific Antigen in The Diagnostic Gray Zone of Total Prostate-Specific Antigen", Urol., Vol. 46: 187-194, 1995. This reflex method eliminates the need for about one-third of those patients with benign disease to undergo such a biopsy. For those patients in the gray diagnostic zone, the method comprises four steps. First, one measures the total PSA level in the blood or serum of the patient. Second, one measures the free PSA level in the blood or serum of a patient, but only if he has a total PSA level of between about 2.5 ng/mL and about 10.0 ng/mL. If the patient has a total PSA level below 2.5 ng/mL, then he is diagnosed to have BPD. If the patient has a total PSA level above 10.0 ng/mL, then he is presumed to have CAP and must be biopsied. Third, one calculates the proportion of free PSA to total PSA. Fourth and finally, one diagnoses the patient as having BPD if the calculated proportion of free PSA to total PSA is greater than about 25%.
Another recent significant advance in diagnosing CAP in a male human patient is disclosed by Chen et alia in "Using Proportions of Free to Total Prostate-Specific Antigen, Age, and Total Prostate-specific Antigen to Predict the Probability of Prostate Cancer", Urol., Vol. 47(4): 518-524, 1996. The Chen reflex method comprises four steps. The total prostate specific antigen (PSA) level in the blood or serum of the patient is measured. If the patient has a total PSA level of between 2.5 ng/mL and 20.0 ng/mL, then the free PSA level in the blood or serum of the patient is measured. The proportion of free PSA to total PSA is calculated. If this proportion is less than about 7%, then the patient is diagnosed as having CAP.